Heart disease continues to be a global medical challenge and a major cause of mortality. Many forms of heart disease are accompanied by hypertrophy and remodeling of the myocardium that increases the risk of sudden cardiac death, making ventricular hypertrophy a leading predictor of contractile dysfunction and progressive heart failure. Inherited cardiomyopathies represent a significant subset of hypertrophic heart disease, the two primary forms being hypertrophic and dilated cardiomyopathy (HCM & DCM, respectively). HCM is characterized by a concentric hypertrophy (thickening) of cardiomyocytes (CMs) and ventricular walls leading to diastolic dysfunction, while DCM is characterized by eccentric CM hypertrophy (lengthening) and chamber dilation with systolic dysfunction. Concentric HCM remodeling is often associated with sarcomeric mutations that confer a gain of mechanical function, whereas dilated DCM remodeling is more typically associated with loss-of-function sarcomeric mutations or mutations in genes encoding cytoskeletal proteins that may mediate mechanotransmission or mechanotransduction in CMs. Our overall hypothesis is that differential hypertrophic responses are regulated by the anisotropy of mechanical force transmission and external loading relative to the myofibrillar axis such that mechanical alterations redistribute the axial versus radial components of CM stress and strain (i.e., change the anisotropy of CM mechanics) are converted into signals that differentiate anisotropic CM growth via distinct mechanosensors and mechanotransducers. Molecular complexes in the membrane and cortical cytoskeleton of CMs are thought to serve as peripheral mechanosensors or transducers that likely mediate differential hypertrophic responses. One such structure is the costamere, which links the sarcomere to the cell membrane and contains vinculin and filamin C (FLNC). A loss of vinculin in mouse hearts was found to cause DCM which was preceded by a reduction of cortical membrane stiffness that led to an increase in radial systolic strain but not axial systolic strain in CMs. It is unknown if a loss of FLNC in the heart also dysregulates cortical stiffness and anisotropy of systolic strain in CMs, but it has been shown that a loss of filamin in fibroblasts reduces the anisotropy of intracellular force distributions in response to applied external mechanical loading. My goal in this project is to employ a new mouse model with cardiac-specific and inducible FLNC deletion and integrate nanoscale measurements of cytoskeletal mechanics, costameric loading distributions, and mechanosensitive gene expression to test the hypothesis that FLNC regulates the relationship between cortical cytoarchitecture, the anisotropy of intra-myocyte strain, and the transduction mechanical stimuli into differential growth that underpins DCM. Using FLNC-null CMs, I will elucidate the dependence of the anisotropy of forces in the cortical cytoskeleton on hypertrophic signaling in CMs and inform novel mechanobiological targets for the treatment or prevention hypertrophic heart disease.
Heart disease continues to be a leading cause of mortality in developed countries, and it is often accompanied by ventricular growth and remodeling that accelerates heart failure. Remodeling of the heart is triggered by mechanically sensitive proteins in cardiac muscle cells that transduce abnormal mechanical signals (often due to mutations or deletions in cytoskeletal or sarcomere proteins) into genetic outputs that progress the pathological growth. The research project I propose here will leverage nanoscale mechanical measurements and structural analyses of cardiac muscle cells in which a cytoskeletal protein has been deleted to uncover molecular mechanisms of the regulation of hypertrophic signaling via cytoskeletal mechanotransduction, with the long-term goal of discovering novel treatments that can prevent or attenuate the detrimental effects of mechanically induced pathological remodeling in the heart.
